The overall goal of this proposal is to determine the role of the insulinotropic GI hormone glucagon-like peptide 1 (GLP-1) in persons with normal glucose tolerance, and with type 2 diabetes. In normal subjects the action of GLP-1 and other gut factors accounts for 30-60 percent of the insulin secreted after eating. This effect is severely impaired in persons with type 2 diabetes suggesting defects in the secretion or action of gut peptides. In addition to its action on the -cell, we have recently observed a novel effect of GLP-1 to suppress endogenous glucose production (EGP) independent of its effects on islet hormone secretion. When given to persons with type 2 diabetes in pharmacologic amounts, GLP-1 normalizes both fasting and post-prandial hyperglycemia, and so has potential as a therapeutic agent. Therefore, it is important to understand the mechanisms by which GLP-1 lowers blood glucose levels in persons with diabetes, and whether defects in the secretion or action of the hormone contribute to the pathogenesis of diabetes. The specific aims of this project are to determine: 1) the mechanism by which GLP-1 normalizes fasting hyperglycemia in diabetic subjects. 2) whether GLP-1 suppresses EGP by inhibition of glycogenolysis, gluconeogenesis, or both. 3) whether the deficient incretin effect in persons with type 2 diabetes is due to decreased levels of GLP-1, or impaired sensitivity of insulin secretion to GLP-1. To address these aims: 1) Glucose turnover will be measured in diabetic subjects before and during GLP-1 infusions, to determine the contributions of islet hormones, and islet hormone-independent effects of GLP-1 to lower blood glucose. 2) EGP will be measured in healthy subjects, and rates of gluconeogenesis and glycogenolysis determined before and after GLP-1 using the 2H2O method. 3) Secretion, and metabolism of GLP-1 in diabetic and control subjects will be compared using a new assay we have developed with greatly increased specificity for GLP-1. In addition, GLP-1 will be infused over a wide range of doses to measure the sensitivity of the insulin response in diabetic and control subjects. The results of these studies will expand the understanding of glucose homeostasis, and promote the development of new strategies to treat type 2 diabetes.